Undernutrition, microbiota maturation, and adaptive immunity in Bangladeshi children

孟加拉国儿童的营养不良、微生物群成熟和适应性免疫

• 批准号: 10718949
• 负责人: Benjamin Lee
• 金额: $ 48.23万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718949
• 关键词: 10 year old; 2 year old; 5 year old; Achievement; Acute; Address; Adult; Affect; Age; Anthropometry; Bangladesh; Bangladeshi; Biological Markers; Birth; Cells; Cessation of life; Child; Child Development; Child Mortality; Childhood; Chronic; Cohort Studies; Communicable Diseases; Communities; Conceptions; Cross-Sectional Studies; Cryopreservation; Data; Defect; Development; Diarrhea; Disease; Evaluation; Failure; Feces; Goals; Growth; Growth and Development function; Health; Human; Immune; Immune system; Immunologics; Impairment; Infection; Inflammation; Inflammatory; Interdisciplinary Study; Intervention; Knowledge; Lead; Life; Longitudinal Studies; Longitudinal cohort; Maintenance; Malnutrition; Measures; Mediating; Metabolic Pathway; Metabolism; Methodology; Methods; Minority; Modeling; Morbidity - disease rate; Nature; Neurocognitive; Organ; Outcome; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Pneumonia; Predisposition; Principal Investigator; Process; Public Health; Research Design; Resource-limited setting; Risk; Role; Sampling; Shapes; Structure; T-Cell Development; T-Lymphocyte; T-cell diversity; T-cell receptor repertoire; Taxonomy; Testing; Underweight; Weight; Work; adaptive immunity; fecal microbiota; gut inflammation; gut microbiota; high risk; immunological diversity; improved; infection risk; innovation; insight; intestinal maturation; longitudinal dataset; metagenomic sequencing; microbiome; microbiota; mortality; obesity risk; pathogen exposure; prevent; proteogenomics; systemic inflammatory response

PROJECT SUMMARY/ABSTRACT Benjamin Lee, MD – Principal Investigator (PI) Childhood undernutrition affects approximately 200 million children around the world and is associated with increased risk of child mortality from infectious diseases. It is generally accepted that undernutrition, as manifested by growth impairment, causes functional immune deficiency that increases susceptibility to severe infections. However, other than in the most extreme form of severe acute malnutrition (SAM), an immunologic basis for this increased risk in undernourished children has yet to be convincingly demonstrated. This may be due in part to previous methodologic limitations, such as reliance on cross-sectional evaluations that cofounded identification of children at highest risk and use of rudimentary methods of immune assessment. This project will address this knowledge gap via longitudinal evaluation of underexplored aspects of pediatric immune development in undernourished and healthy children from a birth cohort study conducted in Dhaka, Bangladesh (PROVIDE). In Aim 1, the multidisciplinary research team will first use stool metagenomic sequencing to investigate the critical contribution of gut microbiota maturation to growth phenotype during the first 2 years of life, and persistence of these effects into later childhood. Children with SAM from this community have previously demonstrated impaired microbiota maturation. This study will assess whether similar perturbations, along with measures of diversity, taxonomic community structure, and metabolic pathways may affect children with other forms of growth impairment, including growth failure, stunting, and underweight. In Aim 2, the project will evaluate measures of T cell diversity and systemic inflammation in these children, along with exploratory analyses using single-cell proteogenomics to identify immune cell profiles unique to each growth phenotype. Finally, the impact of the gut microbiota on these immune outcomes will be investigated. This project will use careful case selection in a well-characterized longitudinal cohort to address critical knowledge gaps relating to undernutrition, microbiota development, and development and maintenance of immune diversity. The knowledge gained herein will provide a major contribution to basic understanding of fundamentally important aspects of the “first 1000 days of life,” the window period from conception to age 2 most critical for establishment of healthy growth and development in children. Ultimately, this work may help inform needed interventions to improve children and development, particularly in resource-limited settings where undernutrition and child mortality due to infections is most prevalent.

项目摘要/摘要 医学博士本杰明·李（Benjamin Lee） - 首席研究员（PI） 童年不足会影响世界各地约2亿儿童，并且与 感染疾病的儿童死亡风险增加。人们普遍认为，营养不良 由于生长障碍而表现出来，引起功能性免疫缺陷，使对严重的敏感性增加 感染。但是，除了最极端的严重急性营养不良（SAM）以外，免疫学 营养不良的儿童的风险增加的基础尚未令人信服。这可能是 部分归因于以前的方法学局限 鉴定有最高风险的儿童和使用基本的免疫评估方法。这个项目将 通过纵向评估小儿免疫的纵向评估来解决此知识差距 在孟加拉国达卡进行的一项出生队列研究中营养不良和健康的孩子的发展 （提供）。在AIM 1中，多学科研究团队将首先使用粪便元基因组测序 研究肠道菌群成熟对在最初2年中生长表型的关键贡献 生命和这些影响的持久性在后来的童年中。来自这个社区的山姆的孩子以前有 证明了菌群成熟的受损。这项研究将评估类似的扰动以及 多样性，分类社区结构和代谢途径的措施可能会影响儿童与其他 在AIM 2中，该项目将评估增长障碍的形式，包括增长失败，发育迟缓和体重不足。 这些儿童的T细胞多样性和全身性炎症的测量，以及使用探索性分析 单细胞蛋白质组学鉴定每个生长表型独有的免疫细胞谱。最后，影响 将研究这些免疫结局的肠道菌群。该项目将使用仔细的案例选择 在一个良好的纵向队列中，以解决与营养不良有关的关键知识差距， 微生物群的开发以及免疫多样性的发展和维持。这里获得的知识 将为对“第一个1000”的根本重要方面的基本理解做出重大贡献 生命的日子，“从概念到2岁的窗户时期对于建立健康增长和 儿童的发展。最终，这项工作可能有助于告知所需的干预措施，以改善儿童和 开发，特别是在资源有限的环境中，由于感染不足和儿童死亡率 最普遍。